Alzheimer's disease (AD) is the most common cause of age-related cognitive decline, affecting greater than 12 million individuals worldwide (Citron M (2002) Nat. Neurosci 5, Suppl 1055-1057). The earliest stages of the disease are characterized by a progressive loss of memory with associated cognitive decline and language and behavioural deficits. In the later stages of the disease, patients develop global amnesia and have greatly reduced motor function. Death typically occurs 9 years following diagnosis and is often associated with other conditions, typically pneumonia (Davis K. L. and Samules S. C. (1998) in Pharmacological Management of Neurological and Psychiatric Disorders eds Enna S. J. and Coyle J. T. (McGraw-Hill, New York pp 267-316)). Current therapies represent symptomatic approaches, focussing on alleviating the cognitive impairment and ameliorating the behavioural symptoms associated with the progressing disease aetiology. In practice these treatments provide only a short lived cognitive benefit with the level of cognitive impairment reported only to last up to 2 years. The potential for a disease-modifying therapy that slows and possibly halts the progression of the disease is enormous. Such approaches would provide radical and sustained improvements to the quality of life of patients and importantly their carers as well as reducing the huge overall healthcare costs of this disease.
Clinical diagnosis of Alzheimer's disease is based upon a combination of physical and mental tests which lead to a diagnosis of possible or probable Alzheimer's disease. At post mortem the disease is confirmed by well characterised neurological hallmarks in the brain, which include the deposition of Aβ in parenchymal plaques and cerebral vessels, intraneuronal formation of neurofibrillary tangles, synaptic loss and loss of neuronal subpopulations in specific brain regions (Terry, R D (1991) J Neural Trans Suppl 53: 141-145).
A plethora of genetic, histological and functional evidence suggests that the β-amyloid peptide (Aβ) is key to the progression of Alzheimer's disease (Selkoe, D. J. (2001) Physiological Reviews 81: 741-766).
Aβ is known to be produced through the cleavage of the beta amyloid precursor protein (also known as APP) by an aspartyl protease enzyme known as BACE1 (also known as β-secretase, Asp2 or Memapsin-2) (De Strooper, B. and Konig, G. (1999) Nature 402: 471-472). In addition to the parenchymal and vascular deposition, soluble oligomeric forms of Aβ have been postulated to contribute to the onset of AD and they may affect neuronal function initially by impairing synaptic function (Lambert et. al. (1998) Proceedings of the National Academy of Science, U.S.A. 95: 6448-6453). Although insoluble amyloid plaques are found early in AD and in MC1, the levels of soluble Aβ aggregates (referred to as oligomers or Aβ-derived diffusible ligands (ADDLs) are also increased in these individuals, and soluble Aβ levels correlate better with neurofibrillary degeneration, and the loss of synaptic markers than do amyloid plaques (Naslund et. al. (2000) J Am Med Assoc 283: 1571-1577, Younkin, S. (2001) Nat. Med. 1: 8-19). The highly amyloidogenic Aβ42 and aminoterminally truncated forms Mx-42 are the predominant species of Aβ found in both diffuse and senile plaques (Iwatsubo, T (1994) Neuron. 13:45-53, Gravina, S A (1995) J. Biol. Chem. 270:7013-7016) The relative levels of Aβ42 appear to be the key regulator of Aβ aggregation into amyloid plaques, indeed Aβ42 has been shown to aggregate more readily that other Aβ forms in vitro (Jarrett, J T (1993) Biochemistry. 32:4693-4697) and as such Aβ42 has been implicated as the initiating molecule in the pathogenesis of AD (Younkin S G, (1998) J. Physiol. (Paris). 92:289-292). Although Aβ42 is a minor product of APP metabolism, small shifts in it's production are associated with large effects on Aβ deposition therefore it has been postulated that reduction of Aβ42 alone may be an effective way of treating AD (Younkin S G, (1998) J. Physiol. (Paris). 92:289-292) In support of this, mutations in the amyloid precursor protein (APP) and presenilin genes have been reported to predominantly increase the relative levels of Aβ42 and therefore shortening the time to onset of Alzheimer's disease (AD) (Selkoe D. J., Podlisny M. B. (2002) Annu. Rev. Genomics Hum. Gemet. 3:67-99). It should be noted however, that the rate of deposition is also dependant on catabolism and Aβ clearance.
Animal models of amyloid deposition have been generated by overexpressing mutant human transgenes in mice. Mice overexpressing single human APP transgenes typically develop cerebral plaque-like β-amyloid deposits from 12 months of age (Games D. et al., (1995) Nature 373: 523-527; Hsiao K. et al., (1996) Science 274: 99-102)), while mice carrying both mutant human APP and presenilin-1 (PS-1) transgenes typically develop cerebral plaque-like β-amyloid deposits as early as 2 months of age (Kurt M. A. et al., (2001) Exp. Neurol. 171: 59-71; McGowan E. et al., (1999) Neurolbiol. Dis. 6: 231-244.
It has become increasingly apparent that the transport of exogenous Aβ between the central nervous system (CNS) and plasma plays a role in the regulation of brain amyloid levels (Shibata, et al (2000) J Clin Invest 106: 1489-1499), with CSF Aβ being rapidly transported from CSF to plasma. Therefore active vaccination with Aβ peptides or passive administration of specific Aβ antibodies rapidly binds peripheral Aβ altering the dynamic equilibrium between the plasma, CSF and ultimately the CNS. Indeed there are now a plethora of studies demonstrated both these approaches can lower Aβ levels, reduce Aβ pathology and provide cognitive benefit in various transgenic models of amyloidosis. Limited studies have also been conducted in higher species. Caribbean vervet monkeys (16-10 years old) were immunised with Aβ peptide over 10 months. Aβ40 levels were elevated 2-5 fold in the plasma which peaked at 251d while the CSF levels of Aβ40 and Aβ42 were significantly decreased by 100d and returned towards baseline thereafter. This reduction in CSF was accompanied by a significant reduction in plaque burden (Lemere, Calif. (2004) Am J Pathology 165: 283-297). Similar increases in plasma Aβ levels were also detected following immunisation of aged (15-20 year old) Rhesus Monkeys (Gandy, S (2004) Alzheimer Dis Assoc Disord 18: 44:46.
The first immune therapy targeting brain amyloid was Elan/Wyeth's AN-1792, an active vaccine. This treatment was terminated following the development of clinical signs consistent with meningoencephalitis. Subgroup analyses suggested that treatment slowed the decline of cognitive function (Nature Clin Pract Neurol (2005) 1:84-85). Post-mortem analysis of patients also showed evidence of plaque-clearance (Gilman S. et al, (2005) Neurology 64 (9) 1553-1562). Bapineuzumab (AAB-001, Elan/Wyeth), a passive MAb therapy has been shown to significantly improve cognition scores in a small phase I safety study.
Other diseases or disorders characterised by elevated β-amyloid levels or β-amyloid deposits include mild cognitive impairment (MC1, Blasko I (2006) Neurobiology of aging “Conversion from cognitive health to mild cognitive impairment and Alzheimer's disease: Prediction by plasma amyloid beta 42, medial temporal lobe atrophy and homocysteine” in press, e-published 19 Oct. 2006), hereditary cerebral haemorrhage with β-amyloidosis of the Dutch type, cerebral β-amyloid angiopathy and various types of degenerative dementias, such as those associated with Parkinson's disease, progressive supranuclear palsy, cortical basal degeneration and diffuse Lewis body type of Alzheimer's disease (Mollenhauer B (2007) J Neural Transm e-published 23 Feb. 2007, van Oijen, M Lancet Neurol. 2006 5:655-60) and Down syndrome (Mehta, PD (2007) J Neurol Sci. 254:22-7).